Cell line- and patient-derived xenograft models
Rodent models of cancer and the pharmacodynamic/pharmacokinetic information they provide are critical to understanding cancer pathophysiology, identifying new targets and therapies, and exploring mechanisms of drug resistance . Xenografts in particular are the most widely used in vivo model for investigating tumor growth rates and metastasis, and can further be subdivided into cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models . CDX models are produced by subcutaneously injecting cancer cell lines into immunodeficient mice, which is a simple process resulting in comparatively rapid tumor formation . One limitation of CDX models, however, is that they do not represent the tumor heterogeneity of individual patients and therefore may not accurately predict the drug response of the original tumor of interest . In contrast, PDX models are generated by implanting cancerous tissue from patients into mice, thus maintaining tumor histopathology and genetics at the trade-off of higher maintenance costs [6, 7].
Although PDX models can be excellent tools for chemotherapeutic drug studies, an intact immune system is required for assessing cancer immunotherapies. Therefore, mice with human immune systems (i.e., “humanized mice”) are necessary for screening immunotherapeutics . Humanized mouse models are produced by implanting human hematopoietic stem cells, tissues, or lymphocytes into immunodeficient mice, from which humanized PDX models can be generated upon implantation with fresh human tumor fragments [7, 8]. In addition to its applications in cancer immunotherapy research, humanized PDX models have also been used to study interactions between tumor and immune cells in the TME . Models like MiXeno also offer an alternative, simpler solution to the full stem cell reconstitution approach while still providing a unique opportunity for studying immunotherapies within a human TME.
Genetically engineered mouse models
In addition to CDX and PDX models, GEMMs are also commonly used in immuno-oncology research. Tumorigenesis in GEMMs is induced by promoting oncogene expression or deleting tumor suppressor genes by genetic engineering . Unlike xenograft models, GEMMs form orthotopic tumors in immune-proficient microenvironments, thereby simulating the tumorigenesis process. However, these models cannot accurately predict interactions between the tumor and human immune system . Many drug candidates that exhibit good therapeutic efficacy at the preclinical stage do not translate well into clinical practice, further highlighting the need for animal models that have humanized immune systems, such as HuGEMM, which are engineered to express humanized drug targets (e.g., genes encoding for immune checkpoint proteins).
As each in vitro and in vivo cancer model has its own advantages and limitations, the choice of model used in cancer immunotherapy research should be selected with the study design and rationale in mind. For example, certain systems are well-suited for high-throughput preliminary screening of compounds of interest, while others are more appropriate at later stages of drug discovery. Crown Bioscience in particular offers many different cancer model systems and services to support drug development in the discovery, preclinical, or translational phase. For a deep dive into the cancer-immunity cycle, T cell biology, suppressive TME compartments, and advanced models and techniques for assessing cancer immunotherapeutics, click the button below to sign up for Crown Bioscience’s webinar series!